Can We Predict Renal Function Recovery After Pyeloplasty in Pediatrics with Ureteropelvic Junction Obstruction? A Systematic Review

Chronic unilateral renal obstruction, primarily caused by ureteropelvic junction obstruction (UPJO), poses challenges in determining the optimal timing for corrective surgery. The goal is to preserve renal function and alleviate symptoms, but there is no definitive diagnostic test to reliably predict the outcomes of surgery. This systematic review aimed to identify predictors for renal function recovery after pyeloplasty in order to guide effective treatment options. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A literature search was performed on PubMed, Embase, and Scopus using keywords related to renal function, pyeloplasty, and predictors. The search was conducted on March 10, 2022. The quality of the included studies was assessed using the Newcastle–Ottawa Scale. Out of 344 potentially relevant articles, 11 met the eligibility criteria for this study. These included 6 retrospective and 5 prospective studies, with a total of 925 participants. Most studies evaluated renal function using differential renal function (DRF). The overall quality of the included studies was considered average. The findings indicated that age at the time of surgery and gender did not significantly influence functional recovery after pyeloplasty. However, preoperative DRF consistently emerged as a critical predictor. Preoperative DRF can serve as the most common predictors used for renal function recovery following pyeloplasty. These findings contribute to understanding effective treatment options for chronic unilateral renal obstruction. However, further research for each predictor is needed to validate these predictors and their clinical utility.


Introduction
Chronic unilateral renal obstruction is more frequently caused by ureteropelvic junction obstruction (UPJO).Preserving renal function from deteriorating and relieving symptoms are the treatment goals for UPJO patients. 1,2Literature has reported that patients with lower renal function preoperatively were less likely to improve, and differential renal function (DRF) would unlikely improve after the alleviation of the obstructions. 3,4eatment for UPJO is still debatable, owing to the confusion regarding postoperative renal function recovery. 5Based on literature, pyeloplasty is indicated for patients with reasonable DRF rather than a poorly functioning kidney (PFK) with a cutoff <10%. 6The current diagnostic examinations, such as ultrasonography, biological markers, magnetic resonance imaging, and drainage or the split function on the diuretic scan, cannot be utilized to predict renal units that might have benefits of surgery from preserved or improved renal function; therefore, the timing to surgically correct UPJO (presumed) is still controversial. 7As a result, experts in urology and nephrology use preoperative or management predictors to help in decisionmaking about conducting nephrectomy or pyeloplasty. 8This study's objective was identifying predictors for the capability of renal function recovery following a pyeloplasty.

Eligibility Criteria
This systematic review includes studies if they met the following criteria: (1) published in English and available in full-text, (2)  published up to January 2022, (3) the studies were randomized controlled trials (RCTs) or observational studies, (4) participants were below 18 years old (pediatric), (5) underwent pyeloplasty, (5) the studies reported the predictors of successful pyeloplasty.We exclude studies that did not include differential renal function (DRF) as preoperative and postoperative renal function evaluation.

Guidelines
This study used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) scale. 9The flow diagram is shown in Figure 1.

Search Strategy
Following PRISMA guidelines, we conducted a literature search on PubMed, Embase, and Scopus.We performed literature search on March 10, 2022, with terms including ("renal" AND "function" AND "pyeloplasty" AND ("predict*" OR "factor*")).We followed the Cochrane Handbook for systematic reviews of interventions guidelines for the search. 10

Quality Assessment and Risk of Bias
Case-control and prospective cohorts were evaluated using the Newcastle-Ottawa Scale for their quality.The studies are judged based on 3 standpoints: study group selection, comparability between groups, and the assessment of exposure and outcome of interest.For bias evaluation, low risk is scored as ≥7, moderate as between 4 and 6, and high risk as ≤3. 11

Data Extraction
One reviewer selected literature and extracted data into an Excel database.Titles and abstracts screening were conducted to determine the eligible articles by 2 authors.Then, a full-text review was performed to find detailed information.Data were extracted by 2 authors independently.Information on the author, study design, publication year, population, sample size, age, type of procedure performed, predictor factors, diagnostic modalities, and renal function tests were extracted to MS Excel.Any disagreements were thoroughly discussed until an agreement was finally reached between the observers.

Study Selection
In total, 344 potential articles were included from the systematic search of all databases (Figure 1).We examined and excluded duplicates, leading to 176 articles.Furthermore, a total of 93 articles were eligible for this study.We included 11 articles following full-text reviews.

Study Characteristics
The study characteristics are shown in Table 1.Six studies consisted of retrospective, and 5 were prospective in study design.The number  of included participants in each study varied, with a total of 925 male-to-female ratios of 2.5 : 1.
Nine studies used Anderson-Hynes dismembered pyeloplasty technique, and 1 study used both dismembered and non-dismembered techniques for comparison.Three out of 11 studies did not mention the side of pyeloplasty, and 7 out of 8 remaining studies reported a higher number of left-sided pyeloplasty than right one.

Quality Assessment
We evaluated the quality and risk of bias by using Newcastle-Ottawa Scale. 11We evaluated each study and recap each of them as seen in Figure 2. The quality was considered average for the included studies.One study was considered low risk for bias, 9 had a moderate bias, and 1 had a high risk of bias.Therefore, the result showed a relatively moderate chance of bias.A meta-analysis of this study could not be conducted because the collected studies were heterogeneous, including the isotype used for DRF evaluation and study population.

Renal Function Test
Nowadays, multiple laboratory workups are available to investigate and evaluate kidney function.Clinically, renal function is most commonly assessed using the GFR estimation modality. 12In this review, several methods were used to evaluate renal function, consisting of DRF or split renal function (SRF), estimated glomerular filtration rate (eGFR), and relative renal function.
All studies used DRF or SRF to compare the pre-and post-pyeloplasty renal function in patients with UPJO.Split renal function (DRF) is 1 kidney's contribution relative to the total renal function.It is useful to evaluate and guide treatments for various renal disorders.Differential renal function can be evaluated using renal scintigraphy with radionuclides such as 99m Tc-DMSA, 99m Tc-MAG3, and 99m Tc-DTPA. 13ecreased split function is considered a functional deterioration of the kidney, although the split function can also be decreased without deterioration of the kidney's absolute function.A study by Piepsz et al 14 showed that decreased split function was not associated with decreased single kidney glomerular filtration rate.
The second method used by studies eGFR Glomerular filtration rate is crucial in assessing renal function in clinical practice, research, and published health practice.The reference standard is the measured GFR, although major advances in eGFR have been shown in the last 20 years. 15ditional methods consisted of the renal resistive index, residual renal function, and renal parenchymal volume.The renal resistive index is a prognostic marker in vascular diseases affecting the kidney, which is nonspecific.It has been proposed that the renal resistive index, as determined by duplex ultrasonography, is a good predictive tool for identifying individuals who would not benefit from revascularization in terms of improved renal function or blood pressure.A high score for resistive index (>0.8) in native kidneys is related to kidney dysfunction and adverse cardiovascular effects. 16In patients who underwent renal surgery, decreased renal function in a few months following the surgery is best associated with decreased parenchymal volume of the kidney.Volume loss estimation can be beneficial in predicting postoperative renal function in those who will undergo surgical intervention with a solitary kidney. 17

Predictive Factors for Renal Function Improvement Post Pyeloplasty
Studies in this review discovered several predictors for renal function recovery post pyeloplasty (Tables 2, 3 and 4).The first factor was the age at diagnosis and surgery.A study by Nodenstrom et al 18 suggested that antenatally-detected patients had a better DRF improvement or catch-up.0][21] Salem et al 22 showed that the overall likelihood of reduced or improved preoperative DRF becoming reduced or improved in the postoperative period is not affected by age.All studies that explored the correlation between gender and results of pyeloplasty found that no association exists between the 2. [19][20][21][23][24][25] The most crucial factor affecting postoperative recovery was shown to be preoperative DRF (Table 2). Studietated that in patients with a preoperative DRF of under 40%, the patients' DRFs were more likely   • Parenchymal thickness (P = .001) The pelvic APD postoperatively were significantly lower among the improved cases, while parenchymal thickness was significantly higher among the improved cases.

N/A
Guler et al 19  to improve. 18,21,22,26Harraz et al 21 stated that patients with lower preoperative DRF have more room for kidney recovery than those with a better DRF.Besides DRF, classic conventional markers of renal function such as serum creatinine can be used.Chipde et al 27 also found that recovery could be predicted based on the ratio of protein and creatinine (Pr/Cr) from urine obtained from the renal pelvis.Renal pelvis's Pr/Cr of over 0.5 can be found in all patients with improved DRF after pyeloplasty.Recent study with proteomics has become more important in diagnostic and prognostic tools.Using proteomic analysis, researchers found several other biomarkers of renal injury and dysfunction, potentially predicting the prognosis and treatment of children with PUJO. 28e anteroposterior diameter (APD) of the pelvis was one of the predictors for pyeloplasty (Table 3).Four studies agreed that APD could potentially predict the success of pyeloplasty. 18,19,26,29A higher preoperative APD was associated with a higher probability of surgery failure. 15,18Despite the presence of studies supporting the effect of APD, 3 studies found that APD had no significant effect on the outcomes of pyeloplasty. 20,21,25en, literature has shown the relationship between cortical thickness and the results of pyeloplasty (Table 3). 1,23,26A study stated that parenchymal thickness of ≤0.75 cm was the predictor correlated with renal function deterioration after a pyeloplasty. 23However, this contrasts with the other 2 studies, which stated that cortical thickness has no effect. 21,25Han et al 20 found that patients with a higher preoperative hydronephrosis area-to-renal parenchyma area (HARP) are expected to show decreased postoperative renal function.
Delayed tissue tracer transit (TTT) can predict renal function improvement after pyeloplasty (Table 4).Tissue tracer transit or cortical transit can be defined as the period when the cortical rim is still visible, and practically no subcortical areas activities. 30Song et al 25 showed the chance of renal function improvement of >5% in patients with prior DRF of <45% is 5.9 times more significant with a delayed TTT.Piepsz et al 30 stated patients with impaired cortical transit had a higher DRF improvement probability following a pyeloplasty.Patients who would benefit from pyeloplasty might be marked by prolonged cortical transit combined with poor kidney washout.

Discussion
Hydronephrosis is the most often identified genitourinary abnormality on prenatal ultrasounds.In the past, every child who presented with ureteropelvic junction blockage was given the option of corrective surgery.The last 10 years have seen a gradual shift toward observational care of congenital UPJ blockage.
Our systematic review indicates that operative repair in patients with UPJO has the potential for renal function recovery after a pyeloplasty.Experimental studies demonstrated that renal damage due to chronic obstruction depends on the duration of the obstruction and severity. 31Patients with impaired kidney function could have a stable or an improved renal function as demonstrated during follow-up with diuretic renography (either increase in GRF or SRF), which suggested that early nephrectomy should be avoided without definitive indications, such as infection or malignancy. 32owever, no definitive factors could be shown in predicting Age at the time of surgery (P = .960)APPD, anterior to posterior pelvic diameter; OR, odds ratio; SFU, society for fetal urology; TTT, tissue tracer transit; Pr/Cr, protein-creatinine ratio.
functional recoverability following a pyeloplasty.In the absence of predictors, other researchers have suggested a urinary diversion trial using an internal double-J stent or an external nephrostomy tube.The intervention could be conducted within 4-8 weeks to find the true chance for recovery.However, management is, in turn, much longer and troublesome for patients. 8,33In our systematic review, we evaluated factors that could be predictors for the capability of renal function to recover following a pyeloplasty.From the included studies, several parameters were found to be associated with outcomes of pyeloplasty, namely the age at diagnosis and surgery, APD, preoperative DRF, urinary protein and creatinine ratio, cortical thickness, SFU, TTT, and HARP.
Age at surgery was studied in this review as a predictor of pyeloplasty outcome.Logically, the younger the patient during surgery leads to a better outcome; however, a study by Salem et al. suggested that age did not affect the overall likelihood of preoperatively DRF being reduced or improved postoperatively. 22This result is probably because renal changes are developmental at birth, which are probably fixed in many patients.0][21] On the contrary, Nodenstrom et al 18 showed that patients who were antenatally detected had a better catch-up or improvement in DRF.Onen et al 34 and Ulman et al 35 presented cohorts of individuals with an average age at surgery of 5-6.5 months and claimed DRF recovery after pyeloplasty compared to the mean age of 20 months; however, they did not report how many patients had a DRF improvement of >5.
The next predictor was baseline DRF.Harraz et al 21 showed that improved postoperative DRF was expected in patients with a preoperative DRF of ≤40%, and this result had been reported previously in adult and pediatric cohorts. 1 With less initial DRF, the room for improvement of DRF is also greater.Almodhen et al 36 revealed that no patients with a baseline DRF of more than 45% achieved DRF recovery of over 5% compared to those with under 45% of DRF.Nonetheless, Ortapamuk et al 37 showed that improvement might not occur, particularly in those with a DRF of under 30%.In the case of failed prior pyeloplasty, the decrease of >5% DRF before and after pyeloplasty contributes to the lower chance of functional recovery after redo-pyeloplasty, suggesting that redo-surgery should be performed before DRF has severely deteriorated. 38Cortical thickness has been shown to be a significant factor affecting recovery.The healthy nephrons might explain the capability of recovery by the kidney. 21,38 also assessed the impact of ultrasound evaluation as the predictor factor.Chipde et al 27 found that APD was the most crucial predictor of post-pyeloplasty renal function improvement.A higher preoperative APD was associated with a higher probability of surgery failure.
A study by Kandur et al 39 has shown that a 20 mm APD threshold indicated a severe obstruction and low DRF threshold.Another study also revealed that a 40-mm APD could be a risk of failure in patients receiving a laparoscopic approach. 19Society for fetal urology hydronephrosis grade was also one of the factors associated with pyeloplasty outcomes.In children with congenital hydronephrosis, SFU grade has been shown to be correlated with renal function, in which a higher grade indicates decreased DRF preservation. 40Patients with a higher preoperative SFU grade had a lower postoperative improvement than those with more postoperative improvement. 5Ultrasound evaluation of both cortical thickness and APD measurement in combination with a dynamic renal scan should be the best diagnostic workup and could not replace one another. 18,27struction of the kidney due to UPJ causes a substantial delay in the 99mTc-MAG3 washout, shown as delayed TTT.The renal pelvis' elevated pressure causes declined GFR, and to balance the GFR and filtration fraction, the renin-angiotensin system will then be activated.Nephrons sclerosis and decreased renal function may be caused by chronic activation of the system. 41,42A study by Son et al 25 showed that the statistically significant predictor of improved renal function by over 5% in individuals with a DRF of under 45% was delayed TTT.
Piepsz et al 30 also suggested that prolonged cortical transit duration could provide benefits for a pyeloplasty and with a high chance of DRF improvement.These results suggested that individuals with delayed TTT and decreased DRF should be assessed to undergo surgical repair immediately.
The last factor investigated was the urinary biochemical parameter.This factor can be used to overcome the limitation of ultrasonography and renography.Nowadays, there are several other urine biomarkers that can be used as explained in the previous systematic review. 28As these markers were already review in previous article, we did not compare them further in this article.In this review, we found a simple laboratory evaluation that can be used in remote or rural hospitals.A study by Beharrie et al 43 compared the samples taken from above and below the obstruction.
The results suggested a statistically significant difference between the renal pelvis' and bladder's (protein-creatinine ratio (Pr/Cr). 43his indicates that severe chronic obstruction altering renal function could present as biochemical parameter changes, including sodium fractional extraction, creatinine clearance, and protein excretion leading to proteinuria.Renal dysplasia may be associated with UPJO; furthermore, changed biochemical parameters, such as proteinuria, can be utilized to predict the result of obstruction release.Chipde et al 27 suggested that all individuals with a preoperative Pr/Cr of less than 0.5 showed improved renal function after pyeloplasty.This result may be beneficial in situations with limited resources, where ultrasound and renal urography are not available; however, more studies are needed to determine the cutoff and reliability.
Most of the included studies, which were retrospective, and the heterogeneous characteristics of the study were considered limitations of this study.The nuclear tests for renal function varied between MAG3, DMSA, and DTPA might cause varied results.The included studies' quality was also average based on the design, methodology, and bias risk.Ideally, the next studies should standardize the tools for a gold standard renal function evaluation.
Our systematic review supported that there were several factors associated with the outcome of pyeloplasty.The suggested predictor was the combination of ultrasound evaluation, such as APD and cortical thickness and DRF evaluation prior to surgery.Urinary biomarkers such as protein creatinine ratio taken from the renal pelvis could be beneficial in limited resources, but more studies are required to support this.

Figure 1 .
Figure 1.Study selection using Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

Figure 2 .
Figure 2. The risk of bias assessment using the Newcastle-Ottawa scale.

Table 3 .
Ultrasound Evaluation as Predictive Factor